NEJM CARDIOVASCULAR DISEASE ARTICLES - Part 2 pdf

clinical therapeutics
T h e
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935
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the author’s clinical recommendations.

Amiodarone for Atrial Fibrillation
Peter Zimetbaum, M.D.
From the Division of Cardiology, Beth Is-
rael Deaconess Medical Center, Boston.
Address reprint requests to Dr. Zimet-
baum at Beth Israel Deaconess Medical
Center, 185 Pilgrim Rd., Boston, MA 02215,
or at
N Engl J Med 2007;356:935-41.
Copyright © 2007 Massachusetts Medical Society.
A 73-year-old man with stable coronary artery disease, hypertension, and chronic re-
nal insufficiency presents with recurrent atrial fibrillation at 80 to 90 beats per min-
ute. His symptoms include shortness of breath and fatigue. He has had atrial fibrilla-
tion twice in the past year; with each episode, electrical cardioversion resulted in
marked improvement in his symptoms. His echocardiogram shows symmetric left
ventricular hypertrophy with evidence of diastolic dysfunction. His medications in-
clude warfarin and metoprolol (25 mg twice daily). He is referred to a cardiologist,
who recommends rhythm control with oral amiodarone.
T h e C l i nic a l Probl e m
Atrial fibrillation is the most common cardiac arrhythmia seen in clinical practice.
It currently affects more than 2 million Americans, with a projected increase to

10 million by the year 2050.
1
Atrial fibrillation may occur in a paroxysmal, self-remit-
ting pattern or may persist unless cardioversion is performed. It is rarely, if ever, a
one-time event but can be expected to recur unpredictably. Symptoms, including
palpitations, dyspnea, fatigue, and chest pain, are present in 85% of patients at the
onset of the arrhythmia but often dissipate with rate- or rhythm-control therapy.
2

The morbidity and mortality associated with this disorder relate to these symptoms
as well as to hemodynamic and thromboembolic complications. Strategies to main-
tain sinus rhythm have not been shown to reduce total mortality or the risk of stroke
but have been shown to improve functional capacity and quality of life.
3-5
The fail-
ure to reduce the mortality associated with rhythm-control strategies is in part due
to the toxicity of the therapies used to maintain sinus rhythm.
6
Pathoph y siol o g y a n d E ff e c t of T he r a p y
The actual mechanism of atrial fibrillation is probably a focal source of automatic
firing, a series of small reentrant circuits, or a combination of the two.
7
Atrial fibrilla-
tion is triggered by atrial premature depolarizations, which frequently arise from
muscular tissue in the pulmonary veins or other structures in the left or, less com-
monly, right atrium.
8
Clinical factors such as hypertension, aging, and congestive
heart failure, as well as recurrent atrial fibrillation itself, result in structural changes
in the atria, including dilatation and fibrosis.

9
This type of mechanical remodeling
promotes the development and perpetuation of atrial fibrillation. Continued rapid
electrical firing in the atria also results in loss of the normal adaptive shortening of
atrial and pulmonary-vein myocyte refractory periods in response to the rapid heart
rate, a process called electrical remodeling.
10
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The hemodynamic consequences of atrial fi-
brillation result primarily from the loss of atrio-
ventricular synchrony but also from the rapid rate
and irregularity of the ventricular response.
9
Pa-
tients with clinical syndromes that impair dia-
stolic compliance (e.g., left ventricular hypertro-
phy) are most likely to have functional deterioration
and symptoms, with loss of the atrial contribution
to ventricular filling; such patients are also there-
fore most likely to benefit from restoration of si-
nus rhythm.
The precise mechanism through which anti-
arrhythmic drugs such as amiodarone suppress
atrial fibrillation remains unknown.
11
Amioda-
rone (with its active metabolite, desethylamio-

darone) blocks sodium, potassium, and calcium
channels. It is also a relatively potent noncom-
petitive alpha-blocker and beta-blocker but has no
clinically significant negative inotropic effect.
9,11

At rapid heart rates, sodium channel blockade is
increased.
12
The consequences of these channel-blocking
effects can be demonstrated electrophysiologi-
cally. Most important, potassium-channel block-
ade slows repolarization, causing an increase in
the duration of the action potential and in the re-
fractoriness of cardiac tissue; this has the effect
of prolonging the QT interval (Fig. 1). Amiodarone
is also uniquely effective in preventing experimen-
tally induced atrial electrical remodeling.
13
Cl inic a l E v idence
Amiodarone has consistently been demonstrated
to be superior to other antiarrhythmic medica-
tions for the maintenance of sinus rhythm.
14-16

The Canadian Trial of Atrial Fibrillation random-
ly assigned 403 patients with paroxysmal or per-
sistent atrial fibrillation to treatment with amio-
darone or with propafenone or sotalol.
14

During
a mean follow-up period of 468±150 days, recur-
rence of atrial fibrillation was documented in 63%
of patients taking propafenone or sotalol, as com-
pared with 35% of those taking amiodarone. The
Sotalol Amiodarone Atrial Fibrillation Efficacy
Trial compared the efficacy of sotalol, amioda-
rone, and placebo in 665 patients with persistent
atrial fibrillation.
15
Recurrence of atrial fibrilla-
tion after 1 year was documented in 35% of pa-
tients taking amiodarone, 60% of those taking
sotalol, and 82% of those taking placebo.
Cl inic a l U se
Amiodarone is approved by the Food and Drug
Administration for the treatment of lethal ven-
tricular arrhythmias but not for the management
of atrial fibrillation. Nonetheless, it is widely pre-
scribed for this indication.
17,18
The safe and effective use of amiodarone re-
quires a firm understanding of its unusual phar-
macokinetics as well as the potential for drug
interactions and adverse events. Amiodarone is a
highly lipophilic compound with a large volume
of distribution (66 liters per kilogram of body
weight). This property results in a delayed onset
of action (an interval of 2 to 3 days) and a long
elimination half-life (up to 6 months).

19
As a result,
there is a substantial lag between the initiation,
modification, or discontinuation of treatment
with amiodarone and a change in drug activity.
Amiodarone is metabolized to desethylamioda-
rone in the liver, and its use should be avoided
in patients with advanced hepatic disease. There
is no clinically significant renal metabolism of
amiodarone, and the dose is not affected by re-
nal dysfunction or dialysis. Amiodarone crosses
the placenta in pregnant women and is excreted
in varying amounts in breast milk.
20
Its use should
therefore be avoided in women who are pregnant
or breast-feeding.
Amiodarone is an excellent choice for use in
patients with structural heart disease or conges-
tive heart failure.
9,21
It is generally reserved as an
alternative to other agents for patients without
underlying heart disease, given its multitude of
side effects.
9
Many physicians hesitate to use amio-
darone in young patients because of the concern
about side effects related to long-term use.
Contraindications to the use of amiodarone

include severe sinus-node dysfunction and ad-
vanced conduction disease (except in patients with
a functioning artificial pacemaker). The drug
should also be used cautiously in patients with
severe lung disease (which may interfere with the
detection of adverse effects).
Before choosing amiodarone for the treatment
of atrial fibrillation, clinicians should consider
other options. Rate control alone (i.e., the use of
agents to maintain a slow ventricular response
rate in atrial fibrillation) is often as effective as
rhythm control in managing the symptoms of
this arrhythmia, and it has been shown to be at
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least as effective as rhythm control with respect
to the long-term outcome.
3
Therefore, a trial of
rate control should always be considered. Other
antiarrhythmic drugs, such as sotalol and propafe-
none, should also be considered, with the rec-
ognition that the balance of risks and benefits
for these agents as compared with amiodarone
depends on the clinical setting.
9
Finally, inva-
sive procedures, such as pulmonary-vein isolation,

have an increasing role in the management of this
disorder,
22
although in most cases, these approach-
es have been used only after the failure of other
therapies.
Before initiating treatment with amiodarone,
Prolonged QT interval
Prolonged duration
of action potential
Normal duration
of action potential
Normal duration
of action potential
Normal QT interval
A
Normal
B
Atrial fibrillation
C
Amiodarone treatment
Left
atrium
Sinus
node
01/25/07
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Author

Fig #
Title
ME
DE
Artist
Issue date
COLOR FIGURE
Rev5
Dr. Zimetbaum
Dr. Jarcho
03/01/2007
1
Daniel Muller
Figure 1. Electrophysiological Action of Amiodarone.
During normal sinus rhythm (Panel A), myocardial activation is initiated in the sinus node, with a resulting coordinated wavefront of de-
polarization that spreads across both atria (arrows) to the atrioventricular node and specialized conduction system (green). Atrial fibril-
lation (Panel B) is triggered by atrial premature depolarizations arising in the region of the pulmonary veins (red asterisk) and propa-
gates in an irregular and unsynchronized pattern (arrows). The resulting pattern of ventricular activation is irregular (as shown on the
electrocardiographic recording). Amiodarone (Panel C) has several electrophysiological effects. Chief among these in the control of atri-
al fibrillation is the effect on the potassium channel blockade, which slows repolarization, thus prolonging the action potential and the
refractoriness of the myocardium. Waves of depolarization are more likely to encounter areas of myocardium that are unresponsive;
thus, propagation is prevented. Although the prolongation of the action potential is most apparent on the electrocardiogram as an ef-
fect on the ventricular myocardium (prolonged QT interval), a similar effect occurs in the atria.
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it is critical to establish therapeutic anticoagula-
tion, because the potential exists for conversion
to sinus rhythm (with a consequent risk of throm-

boembolism) at any point during the drug-load-
ing phase. The recommended criterion for anti-
coagulation is an international normalized ratio
(INR) of 2.0 to 3.0 for 3 consecutive weeks or a
transesophageal echocardiogram demonstrat-
ing the absence of left atrial thrombus.
Amiodarone therapy is initiated with a load-
ing dose of approximately 10 g in the first 1 to
2 weeks. This loading dose can be given in divided
doses — for example, 400 mg given orally twice
a day for 2 weeks followed by 400 mg given orally
each day for the next 2 weeks. Reducing the in-
dividual dose and administering it three times
daily may reduce the gastrointestinal intolerance
sometimes associated with amiodarone loading.
A more protracted loading period with a lower
daily dose may be used when sinus- or atrioven-
tricular-node dysfunction is a concern.
It is relatively safe to initiate treatment with
amiodarone in the ambulatory setting.
23
Electro-
cardiographic monitoring (with 12-lead electro-
cardiography or an event recorder) should be per-
formed at least once during the loading period to
evaluate the patient for excessive prolongation of
the QT interval (>550 msec) or bradycardia. Pro-
longation of the QT interval is common and gen-
erally responds to dose reduction.
15

Given the delay in the onset of antiarrhythmic
action with amiodarone, it is common for atrial
fibrillation to persist or recur during the loading
phase of drug administration; however, this does
not predict rates of sinus rhythm at 1 month.
24

Approximately 30% of patients have a reversion
to sinus rhythm during this loading phase, and
the remainder can undergo electrical cardiover-
sion, which has a high rate of success.
15,23
Once the loading phase is completed, the main-
tenance dose of amiodarone for atrial fibrillation
is 200 mg a day. Monitoring of levels of amioda-
rone or desethylamiodarone is not recommended,
given the lack of correlation between drug levels
and efficacy or adverse events.
12
However, moni-
toring with the use of various laboratory tests
for evidence of adverse effects is recommended.
Amiodarone interferes with the hepatic me-
tabolism of many medications, the most common
of which are digoxin and warfarin. Generally, di-
goxin should be discontinued if possible, or the
dose at least reduced by 50%. The INR must be
monitored closely during amiodarone loading and
maintenance therapy. It is usually necessary to
reduce the warfarin dose by 25 to 50% when the

drug is coadministered with amiodarone.
The cost of amiodarone is typically about $1.25
per tablet in the United States. In addition, the
initial screening tests performed before treatment
begins (chest radiography and tests of pulmonary,
thyroid, and liver function) cost approximately
$250, with a similar expense annually to screen
for adverse effects.
A dv e r se E f f e c t s
Amiodarone is associated with both cardiovas-
cular and noncardiovascular adverse events (Ta-
ble 1). Side effects resulting in discontinuation
of therapy occur in 13 to 18% of patients after
1 year.
12,15
The most frequent cardiovascular side
effect is bradycardia, which is often dose-related,
occurs more frequently in elderly patients than in
younger patients, and can often be mitigated by
dose reduction.
24,25
Prolongation of the QT inter-
val is seen in most patients but is associated with
a very low incidence of torsades de pointes (<0.5%)
as compared with other drugs that prolong the
QT interval (e.g., sotalol and dofetilide).
17
Clinical evidence of hypothyroidism occurs in
up to 20% of patients taking amiodarone. It devel-
ops most often in patients with preexisting auto-

immune thyroid disease and those living in areas
replete with iodine (that is, they are not iodine-
deficient).
26
Hypothyroidism is easily managed
with levothyroxine and generally is not cause for
discontinuing amiodarone.
12,26
Hyperthyroidism
occurs in 3% of patients in areas where dietary
iodine is sufficient but in 20% of patients in
iodine-deficient areas. It can be difficult to rec-
ognize clinically because many of the typical ad-
renergically mediated signs are blocked by amio-
darone. The recurrence of atrial fibrillation during
maintenance amiodarone therapy should prompt
an evaluation for amiodarone-induced hyperthy-
roidism. Management requires the assistance of an
experienced endocrinologist and may require dis-
continuation of amiodarone therapy. Thyrotropin
levels should be checked in all patients before
amiodarone therapy is initiated and at least every
6 months thereafter.
12
Pulmonary toxicity is one of the most serious
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939
complications of amiodarone use. It occurs in less

than 3% of patients and is thought to be related
to the total cumulative dosage.
12
In the Atrial Fi-
brillation Follow-up Investigation of Rhythm Man-
agement study, there was a slightly increased inci-
dence of pulmonary toxicity in patients with
preexisting pulmonary disease, but mortality from
pulmonary causes and overall mortality were not
higher among these patients than among those
without preexisting pulmonary disease.
27
The man-
agement of acute pulmonary toxicity involves dis-
continuation of therapy, supportive management,
and, in extreme cases, corticosteroid administra-
tion.
12
Screening pulmonary-function tests and
chest radiography should be performed at base-
line, and chest radiography should be performed
yearly thereafter.
9,12
Pulmonary-function tests
should be repeated if symptoms develop.
Hepatic toxicity is a rare complication of amio-
darone therapy when the drug is used in low doses.
Amiodarone can cause nonalcoholic steatohepa-
titis, which is manifested as an asymptomatic in-
crease in hepatic aminotransferase levels (more

than two times the upper limit of the normal
range). This condition can generally be reversed by
discontinuing the drug but can result in cirrhosis if
unheeded. Liver-function tests should be measured
at baseline and every 6 months thereafter.
9,12,28
Corneal microdeposits are seen in virtually all
patients receiving long-term amiodarone thera-
py and are rarely of clinical significance.
12
Optic
neuropathy has been reported in less than 1% of
patients, but it may be a result of associated medi-
cal conditions rather than an effect of amioda-
rone. Nonetheless, the potential severity of optic
neuropathy warrants discontinuation of amioda-
rone therapy if the condition is suspected. Oph-
thalmologic examinations are recommended at
baseline only for patients with preexisting ab-
normalities.
Dermatologic side effects of amiodarone use
include photosensitivity, with susceptibility to sun-
burn, particularly in patients with a fair complex-
ion. Avoidance of direct exposure to the sun and
use of sunscreen can diminish this reaction.
A gray-bluish skin discoloration may be seen in
patients who take large doses of amiodarone for
long periods.
29
Alopecia is also an infrequent side

effect of amiodarone.
Neurologic side effects, which occur in up to
Table 1. Adverse Effects of Oral Amiodarone.
Adverse Effect Incidence Recommended Monitoring Special Considerations
Cardiac
Bradycardia
Prolonged QT interval
Torsades de pointes
5%
In most
patients
<1%
Baseline electrocardiogram at least
once during loading period, es-
pecially if conduction disease is
present; yearly thereafter
Consider reduction of loading dose in
elderly patients and those with un-
derlying sinoatrial or atrioventricu-
lar conduction disease; reduce
dose or discontinue if QT interval
exceeds 550 msec
Hepatic 15% Aspartate and alanine aminotrans-
ferase measurements at base-
line and every 6 months there-
after
Avoid in patients with severe liver
disease
Thyroid
Hyperthyroidism

Hypothyroidism
3%
20%
Thyroid-function tests at baseline
and two or three times a year
thereafter
Avoid in presence of preexisting, non-
functioning thyroid nodule; higher
incidence of thyroid effects in pa-
tients with autoimmune thyroid
disease
Pulmonary <3% Pulmonary-function tests at base-
line and if symptoms develop;
chest radiograph at baseline
and yearly thereafter
Discontinue amiodarone immediately
if pulmonary effects suspected
Dermatologic 25–75% Routine Recommend use of sunscreen with a
high sun protection factor
Neurologic 3–30% Routine Consider dose reduction
Ophthalmologic
Corneal deposits
Optic neuritis
100%
<1%
Examination at baseline if there is
underlying abnormality; exami-
nations as needed thereafter
Avoid in presence of preexisting optic
neuritis

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940
30% of patients, include ataxia, tremor, peripheral
polyneuropathy, insomnia, and impaired memo-
ry. These effects are often dose-related and occur
more often in elderly patients than in younger pa-
tients.
A r e a s of U nce r t a in t y
The side effects of low-dose amiodarone therapy
(200 mg daily) in patients taking the drug for
more than 5 years — the duration of clinical stud-
ies that have been conducted — are unknown.
Some patients, particularly those who are elderly
and those with relatively little body fat, can be
treated with a very low dose (100 mg per day).
There are no available data from clinical trials
that support this reduced-dose strategy, but it is
common practice.
Amiodarone is frequently used for the pre-
vention and treatment of atrial fibrillation as-
sociated with cardiac surgery, including the maze
procedure for cure of atrial fibrillation.
9
Atrial
fibrillation associated with cardiac surgery oc-
curs most frequently in the first few days after
surgery but can also occur weeks after surgery.

For patients undergoing cardiac surgery, amio-
darone is given at a dose of 600 mg a day for 1 to
2 weeks before surgery and is continued for 4 to
6 weeks after surgery. Although this approach is
supported by data from clinical trials, beta-block-
ers have also been reported to reduce rates of
postoperative atrial fibrillation,
30
and none of the
major studies of amiodarone compared it with
the use of a beta-blocker alone.
The use of amiodarone in combination with
other antiarrhythmic drugs has not been thor-
oughly studied. One intriguing combination is
that of angiotensin-receptor blockers with amio-
darone. Emerging data suggest that the combi-
nation of these two agents is more effective than
either is alone.
31
Gu i de l i ne s
Recently published guidelines of the American
Heart Association, the American College of Car-
diology, and the European Society of Cardiology
recommend reserving amiodarone as an alterna-
tive agent for most patients with atrial fibrilla-
tion, the exceptions being those who have clini-
cal heart failure or hypertension with substantial
left ventricular hypertrophy.
9
For patients at very

high risk for recurrence of atrial fibrillation (e.g.,
those with severe mitral regurgitation), amioda-
rone may be the best choice of a first-line agent,
given the low likelihood that treatment with oth-
er antiarrhythmic agents will be successful.
R e c om m e nda t ions
For the patient described in the vignette, it is rea-
sonable to attempt to maintain sinus rhythm be-
cause of the presence of symptoms in spite of a
well-controlled ventricular response. His symp-
toms are probably due to diastolic dysfunction.
The presence of coronary artery disease limits
the choice of antiarrhythmic drug to amiodarone,
sotalol, and dofetilide. The patient’s renal insuf-
ficiency makes sotalol and dofetilide unattractive
options. The preferred agent to maintain sinus
rhythm in this patient is therefore amiodarone.
Baseline screening studies should include tests
of liver, thyroid, and pulmonary function as well
as chest radiography. The warfarin dose should
be decreased by at least 25% when the loading
dose of amiodarone is administered. It is reason-
able to initiate amiodarone therapy in the outpa-
tient setting. A slightly reduced loading dose (e.g.,
600 mg per day in one dose or divided doses for
3 to 4 weeks) is reasonable, given that the patient’s
baseline heart rate is already well controlled on
a low dose of a beta-blocker (which may suggest
underlying atrioventricular-node conduction dis-
ease). The patient should undergo electrocardi-

ography weekly or should be discharged with a
loop recorder to monitor heart rhythm, heart rate,
and duration of the QT interval. If conversion has
not occurred by the end of the loading period,
electrical cardioversion should be performed, fol-
lowed by a reduction in the dose of amiodarone
to 200 mg daily. The warfarin dose may need to
be increased as the amiodarone dose is reduced.
No potential conflict of interest relevant to this article was
reported.
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original article
T h e
n e w e n g l a n d j o u r na l o f m e d i c i n e
n engl j med 356;10 www.nejm.org march 8, 2007
1030
Analysis of 14 Trials Comparing Sirolimus-
Eluting Stents with Bare-Metal Stents
Adnan Kastrati, M.D., Julinda Mehilli, M.D., Jürgen Pache, M.D.,

Christoph Kaiser, M.D., Marco Valgimigli, M.D., Ph.D., Henning Kelbæk, M.D.,
Maurizio Menichelli, M.D., Manel Sabaté, M.D., Maarten J. Suttorp, M.D., Ph.D.,
Dietrich Baumgart, M.D., Melchior Seyfarth, M.D., Matthias E. Pfisterer, M.D.,
and Albert Schömig, M.D.
From Deutsches Herzzentrum, Technische
Universität, Munich, Germany (A.K., J.M.,
J.P., M. Seyfarth, A.S.); University of Basel,
Basel, Switzerland (C.K., M.E.P.); Univer-
sity of Ferrara, Ferrara, Italy (M.V.); Rigs-
hospitalet, Copenhagen (H.K.); San
Camillo Hospital, Rome (M.M.); Cardio-
vascular Institute, Hospital de la Santa
Creu i Sant Pau, Barcelona (M. Sabaté);
St. Antonius Hospital, Nieuwegein, the
Netherlands (M.J.S.); and Preventicum–
Klinik für Diagnostik, Essen, Germany
(D.B.). Address reprint requests to Dr.
Kastrati at Deutsches Herzzentrum, Laza-
rettstr. 36, 80636 Munich, Germany, or at

This article (10.1056/NEJMoa067484) was
published at www.nejm.org on February
12, 2007.
N Engl J Med 2007;356:1030-9.
Copyright © 2007 Massachusetts Medical Society.
A B S T R AC T
Background
The long-term effects of treatment with sirolimus-eluting stents, as compared with
bare-metal stents, have not been established.
Methods

We performed an analysis of individual data on 4958 patients enrolled in 14 random-
ized trials comparing sirolimus-eluting stents with bare-metal stents (mean follow-
up interval, 12.1 to 58.9 months). The primary end point was death from any cause.
Other outcomes were stent thrombosis, the composite end point of death or myo-
cardial infarction, and the composite of death, myocardial infarction, or reinter-
vention.
Results
The overall risk of death (hazard ratio, 1.03; 95% confidence interval [CI], 0.80 to
1.30) and the combined risk of death or myocardial infarction (hazard ratio, 0.97;
95% CI, 0.81 to 1.16) were not significantly different for patients receiving siroli-
mus-eluting stents versus bare-metal stents. There was a significant reduction in
the combined risk of death, myocardial infarction, or reintervention (hazard ratio,
0.43; 95% CI, 0.34 to 0.54) associated with the use of sirolimus-eluting stents. There
was no significant difference in the overall risk of stent thrombosis with sirolimus-
eluting stents versus bare-metal stents (hazard ratio, 1.09; 95% CI, 0.64 to 1.86).
However, there was evidence of a slight increase in the risk of stent thrombosis
associated with sirolimus-eluting stents after the first year.
Conclusions
The use of sirolimus-eluting stents does not have a significant effect on overall
long-term survival and survival free of myocardial infarction, as compared with
bare-metal stents. There is a sustained reduction in the need for reintervention after
the use of sirolimus-eluting stents. The risk of stent thrombosis is at least as great
as that seen with bare-metal stents.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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14 Trials of Sirolimus-Elu ting Stents ver sus Bare-Me tal Stents
n engl j med 356;10 www.nejm.org march 8, 2007
1031
R
estenosis after percutaneous cor-

onary intervention (PCI) reduces the qual-
ity of life and increases the morbidity of
patients with this complication
1
; it may even in-
crease the risk of death.
2
Drug-eluting stents are
highly effective in preventing restenosis after PCI.
3

It has been anticipated that by reducing the rate
of restenosis, drug-eluting stents may have the
potential to improve the long-term prognosis of
patients treated with these devices. However, ini-
tial randomized studies focused on restenosis it-
self and had insufficient power and duration to
assess the incidence of less frequent adverse
events, such as death.
Recent reports have identified pathologic re-
sponses of the vessel wall to drug-eluting stents
that may serve as precursors to adverse clinical
events.
4
Such studies have raised concern that
drug-eluting stents might actually worsen, rather
than improve, long-term prognosis. However, ef-
forts to examine this issue by combining data
from previous randomized trials have been limit-
ed to published trial-level data and have not in-

cluded all the relevant studies.
5-7
The aim of this
study was to assess the long-term outcome after
implantation of sirolimus-eluting stents on the
basis of data from individual patients from ran-
domized clinical trials comparing this device with
bare-metal stents.
Me t hods
Inclusion Criteria
We included in our analysis the results of ran-
domized clinical trials that compared sirolimus-
eluting stents (Cypher or Cypher Select, Cordis)
with bare-metal stents for management of coro-
nary artery disease if results for a mean follow-up
period of at least 1 year were reported or made
available by the trials’ investigators or sponsors.
Data Sources
We searched the National Library of Medicine
(PubMed, at www.pubmed.gov), the National In-
stitutes of Health clinical trials registry (www.
clinicaltrials.gov), and the Cochrane Central Reg-
ister of Controlled Trials (www.mrw.interscience.
wiley.com/cochrane/cochrane_clcentral_articles_
fs.html) for randomized trials comparing siro-
limus-eluting stents with bare-metal stents in
patients with coronary artery disease. We also
searched Internet-based sources of information on
the results of clinical trials in cardiology (www.
cardiosource.com/clinicaltrials, www.theheart.

org, www.clinicaltrialresults.com, and www.tctmd.
com), as well as conference proceedings from meet-
ings of the American College of Cardiology, the
American Heart Association, and the European
Society of Cardiology. Relevant reviews and edi-
torials published within the past year in major
medical journals were identified and assessed for
possible information on trials of interest. Searches
were restricted to the period from January 2002
through September 2006.
We found and screened 16 randomized tri-
als,
8-23
the main characteristics of which are
shown in
Table 1
. Two randomized trials, Reduc-
tion of Restenosis in Saphenous Vein Grafts with
Cypher Sirolimus-Eluting Stent (RRISC)
16
and
Sirolimus-Eluting Stent in the Prevention of Re-
stenosis in Small Coronary Arteries (SES-SMART),
19

were not included in this analysis because each
had a mean follow-up of less than 1 year; the
findings of these trials are displayed in
Table 1
of

the Supplementary Appendix (available with the
full text of this article at www.nejm.org).
Data Collection and Quality Assessment
An electronic form containing the data fields to be
completed for individual patients was sent to all
principal investigators or sponsors of the trials.
Data from nine randomized trials
8,11,13,14,17,18,20,22,23

were provided by the principal investigators; data
from the remaining five trials
9,10,12,15,21
were pro-
vided by the sponsor, who had no role in the study
design or analysis or in the writing of or decision
to publish the manuscript.
The data requested for each patient included
the date of randomization, treatment allocation,
diabetes status, event status (including death, myo-
cardial infarction, coronary reintervention [per-
cutaneous or surgical], and stent thrombosis and
the respective dates of occurrence), and the date of
the last follow-up visit. All data were thoroughly
checked for consistency (logical checking and
checking against the original publications). Any
queries were resolved and the final database en-
tries verified by the responsible trial investigator.
We also evaluated each trial for the adequacy
of allocation concealment, performance of the
analysis according to the intention-to-treat prin-

ciple, and blind assessment of the outcomes of
interest. We used the criteria recommended by
Altman and Schulz
24
and by Jüni et al.
25
to de-
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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T h e n e w e n g l a n d j o u r na l o f m e d i c i n e
n engl j med 356;10 www.nejm.org march 8, 2007
1032
Table 1. Main Characteristics of the Trials.*
Study
No. of
Patients
No. of
Patients with
Diabetes
Mean
Age
Double
Blinding Patient Profile Primary End Point
Protocol-Mandated
Follow-up
Angiography
Length of
Thienopyridine
Therapy
Mean

Length of
Follow-up
yr mo
BASKET
8
545 101 64.0 No Unselected patients Cost-effectiveness based on the composite
of death, myocardial infarction, and
reintervention
No 6 18.3
C-SIRIUS
9
100 24 60.5 Yes Small vessels, long lesions Minimal luminal diameter on follow-up
angiography
Yes 2 48.5
DECODE
10
83 83 60.0 No Patients with diabetes Late luminal loss on angiography Yes 3 12.7
DIABETES
11
160 160 66.6 No Patients with diabetes Late luminal loss on angiography Yes 12 25.3
E-SIRIUS
12
352 81 62.3 Yes Long lesions Minimal luminal diameter on follow-up
angiography
Yes 2 49.4
Pache et al.
13
500 154 66.6 No Unselected patients Binary restenosis on angiography Yes 6 46.1
PRISON II
14

200 27 59.5 No Total occlusions Binary restenosis on angiography Yes 6 24.6
RAVEL
15
238 44 60.8 Yes Selected patients Late luminal loss on angiography Yes 2 58.1
RRISC
16
75 11 72.5 No Venous bypass grafts Late luminal loss on angiography Yes 2 6.0
SCANDSTENT
17
322 58 62.7 No Complex lesions Minimal luminal diameter on follow-up
angiography
Yes 12 12.2
SCORPIUS
18
193 193 64.9 No Patients with diabetes Late luminal loss on angiography Yes 3 12.7
SES-SMART
19
257 64 63.4 No Small vessels Binary restenosis on angiography Yes 2 8.0
SESAMI
20
320 65 61.6 No Patients with acute myo-
cardial infarction
Binary restenosis on angiography Yes 12 12.3
SIRIUS
21
1058 279 62.2 Yes Relatively selected patients Death, myocardial infarction, or reintervention Yes 3 58.9
STRATEGY
22
175 26 62.6 No Patients with acute myo-
cardial infarction

Death, myocardial infarction, stroke, or
binary restenosis on angiography
Yes 3 24.2
TYPHOON
23
712 116 59.3 No Patients with acute myo-
cardial infarction
Death from cardiac causes, myocardial
infarction, or reintervention
Yes 6 12.1
* Two randomized trials that are listed in the table — RRISC
16
and SES-SMART
19
— were not included in the analysis because they each had a mean follow-up of less than 1 year.
BASKET denotes Basel Stent Kosten Effektivitäts Trial (ISRCTN.org number, ISRCTN75663024), C-SIRIUS Canadian Study of the Sirolimus-Eluting Stent in the Treatment of Patients with
Long De Novo Lesions in Small Native Coronary Arteries (ClinicalTrials.gov number, NCT00381420), DECODE Randomized Trial of Cypher versus Bare Metal Stents in Diabetics,
DIABETES Diabetes and Sirolimus-Eluting Stent Trial, E-SIRIUS European Multicenter, Randomized, Double-Blind Study of the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent
in the Treatment of Patients with De Novo Coronary Artery Lesions (NCT00235144), PRISON II Primary Stenting of Totally Occluded Native Coronary Arteries II (NCT00258596),
RAVEL Randomized Study of the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions (NCT00233805),
RRISC Reduction of Restenosis in Saphenous Vein Grafts with Cypher Sirolimus-Eluting Stent (NCT00263263), SCANDSTENT Stenting Coronary Arteries in Non-Stress/Benestent
Disease Trial (NCT00151658), SCORPIUS German Multicenter, Randomized, Controlled, Open-Label Study of the Cypher Sirolimus-Eluting Stent in the Treatment of Diabetic Patients
with De Novo Native Coronary Artery Lesions, SES-SMART Sirolimus-Eluting Stent in the Prevention of Restenosis in Small Coronary Arteries, SESAMI Randomized Trial of Sirolimus
Stent vs. Bare Stent in Acute Myocardial Infarction (NCT00288210), SIRIUS Sirolimus-Eluting Balloon Expandable Stents in the Treatment of Patients with De Novo Coronary Artery
Lesions (NCT00232765), STRATEGY Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent vs. Abciximab and Bare-Metal Stent in Myocardial Infarction (NCT00229515), and
TYPHOON Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (NCT00232830).
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
14 Trials of Sirolimus-Elu ting Stents ver sus Bare-Me tal Stents
n engl j med 356;10 www.nejm.org march 8, 2007

1033
cide whether the treatment allocation was ade-
quately concealed. Some trials used a modified
intention-to-treat principle (i.e., excluding patients
who did not receive the study stent) (see Table 2
of the Supplementary Appendix).
Study Outcomes
The primary end point of this analysis was death
from any cause. Secondary end points were the
composite of death or myocardial infarction and
the composite of death, myocardial infarction, or
reintervention (major adverse cardiac events). We
also assessed the occurrence of stent thrombosis
(see Table 2 of the Supplementary Appendix for
the end-point definitions used in individual trials).
It is important to note that in eight trials, data
for patients who underwent target-lesion revascu-
larization were censored with respect to the sub-
sequent assessment of stent thrombosis. The ad-
judication of events in each trial was performed by
the same event committee over the entire follow-
up period.
Statistical Analysis
We performed survival analyses with the use of
the Mantel–Cox test stratified according to trial.
Survival was defined as the interval from random-
ization until the event of interest. Data for pa-
tients who did not have the event of interest were
censored at the date of the last follow-up visit.
The log-rank test was used to calculate hazard

ratios and their 95% confidence intervals (CIs).
Trials in which the event of interest was not
observed in either study group were omitted from
the analysis of that event. For trials in which
only one of the groups had no event of interest,
the estimate of treatment effect and its standard
error were calculated after adding 0.5 to each cell
of the 2×2 table for the trial.
26
We assessed the heterogeneity across trials by
the Cochran test and by calculating the I
2
statis-
tic (describing the percentage of total variation
across trials that was due to heterogeneity rather
than chance), as proposed by Higgins et al.
27
We
pooled hazard ratios from individual trials ac-
cording to the method of DerSimonian and Laird
for random effects.
28
Sensitivity analyses were performed by com-
paring the treatment effects obtained with each
trial removed consecutively from the analysis with
the overall treatment effects. In addition, we used
a random-effects meta-regression analysis to esti-
mate the extent to which including four covari-
ates — the nature of the study with respect to
blinding (double blinding or no double blinding),

the length of follow-up, the protocol-mandated
duration of dual antiplatelet therapy, and the
presence of acute myocardial infarction — as
22p3
0.1 1.0
10.0
Sirolimus Stent
Better
Bare-Metal
Stent Better
Hazard RatioTrial
Sirolimus
Stent
Bare-Metal
Stent
P(heterogeneity)=0.75
I
2
=0%
P(overall effect)=0.80
Probability of Survival (%)
80
90
70
60
50
0
0 1 2 3 4
5
Years after Randomization

Sirolimus stent
Bare-metal stent
100
AUTHOR:
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4-C
H/T
RETAKE
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ICM
CASE
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Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Kastrati
1 of 5
03-08-07
ARTIST: ts
35610

No. of events/total no. of patients
BASKET
C-SIRIUS
DECODE
DIABETES
E-SIRIUS
Pache et al.
PRISON II
RAVEL
SCANDSTENT
SCORPIUS
SESAMI
SIRIUS
STRATEGY
TYPHOON
Overall
10/264
2/50
0/54
7/80
10/175
29/250
2/100
14/120
1/163
5/95
3/160
45/533
10/87
8/355

146/2486
13/281
3/50
2/29
5/80
11/177
24/250
3/100
8/118
1/159
4/98
7/160
46/525
12/88
8/357
147/2472
1.03 (0.80 to 1.30)
A
B
No. at Risk
Sirolimus stent
Bare-metal stent
548
530
1028
1044
765
842
1218
1207

2056
2063
2486
2472
Figure 1. Hazard Ratios for Individual Trials and for the Pooled Population
and Kaplan–Meier Estimates for 5-Year Survival.
In Panel A, hazard ratios are shown on a logarithmic scale. The size of each
square is proportional to the weight of the individual study, measured as the
inverse of the estimated variance of the log hazard ratio. In Panel B, Kaplan–
Meier curves are shown for survival for the pooled population during a 5-year
period in each of the stent groups.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
T h e n e w e n g l a n d j o u r na l o f m e d i c i n e
n engl j med 356;10 www.nejm.org march 8, 2007
1034
inclusion criteria for the trial might have influ-
enced the treatment effect. Using the Mantel–Cox
model, we checked for statistically significant
interaction between the treatment effect (siroli-
mus-eluting stent vs. bare-metal stent) and the
presence of diabetes mellitus (the only prespeci-
fied subgroup that was analyzed).
All P values are two-sided. Results were con-
sidered to be statistically significant at a P value
of less than 0.05. Statistical analysis was per-
formed with the use of Stata software, version 9.2
(Stata). Survival curves are presented as simple,
nonstratified Kaplan–Meier curves across all trials
and constructed with the use of S-Plus software,

version 4.5 (Insightful).
R e s u l t s
Our analysis included 14 trials and 4958 patients,
1411 of whom had diabetes mellitus.
8-15,17,18,20-23

Table 1
displays the main characteristics of these
trials. The age of the patients in the trials ranged
from 59.3 to 66.6 years, and the length of follow-
up ranged from 12.1 to 58.9 months.
Figure 1A shows the absolute numbers of
deaths in each trial according to treatment group,
with the hazard ratio for each trial. There was
no statistical evidence of heterogeneity across the
14 trials. In total, there were 146 deaths (83 from
cardiac causes) in patients with sirolimus-eluting
stents and 147 deaths (79 from cardiac causes)
in patients with bare-metal stents. Overall, the
use of sirolimus-eluting stents was associated
with a hazard ratio for death of 1.03 (95% CI,
0.80 to 1.30; P = 0.80), as compared with that of
bare-metal stents.
Sequential exclusion of each individual trial
from the analysis of death yielded hazard ratios
that ranged from 0.96 (95% CI, 0.74 to 1.25) to
1.06 (95% CI, 0.84 to 1.34) and were not sig-
nificantly different from the overall hazard ratio
(P≥0.71). No significant influence of prespecified
covariates on the treatment effect was observed,

including the length of follow-up (P = 0.44), the
protocol-mandated duration of dual antiplatelet
therapy (P = 0.69), the presence of patients with
acute myocardial infarction in the trial (P = 0.56),
or the presence of double blinding in the trial de-
sign (P = 0.70). Figure 1B shows the overall 5-year
survival curves for the two treatment groups.
Figure 2A shows the absolute numbers of pa-
tients who died or had a myocardial infarction in
each trial according to treatment group, with the
hazard ratio for each trial. There was no statisti-
cal evidence of heterogeneity across the 14 trials.
In total, 241 patients with sirolimus-eluting stents
22p3
0.1 1.0
10.0
Sirolimus Stent
Better
Bare-Metal
Stent Better
Hazard RatioTrial
Sirolimus
Stent
Bare-Metal
Stent
P(heterogeneity)=0.80
I
2
=0%
P(overall effect)=0.76

Probability of Survival Free of Myocardial
Infarction (%)
80
90
70
60
50
0
0 1 2 3 4
5
Years after Randomization
Sirolimus stent
Bare-metal stent
100
AUTHOR:
FIGURE:
JOB: ISSUE:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
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H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.

Please check carefully.
REG F
Enon
1st
2nd
3rd
Kastrati
2 of 5
03-08-07
ARTIST: ts
35610
No. of events/total no. of patients
BASKET
C-SIRIUS
DECODE
DIABETES
E-SIRIUS
Pache et al.
PRISON II
RAVEL
SCANDSTENT
SCORPIUS
SESAMI
SIRIUS
STRATEGY
TYPHOON
Overall
23/264
4/50
1/54

10/80
19/175
38/250
5/100
22/120
4/163
10/95
6/160
74/533
14/87
11/355
241/2486
27/281
7/50
2/29
12/80
22/177
35/250
6/100
12/118
7/159
9/98
10/160
72/525
18/88
13/357
252/2472
0.97 (0.81 to 1.16)
A
B

No. at Risk
Sirolimus stent
Bare-metal stent
516
505
983
992
728
798
1168
1148
1985
1983
2486
2472
Figure 2. Hazard Ratios for Death or Myocardial Infarction and Kaplan–Meier
Estimates for Survival Free of Myocardial Infarction.
In Panel A, hazard ratios are shown on a logarithmic scale. The size of each
square is proportional to the weight of the individual study, measured as the
inverse of the estimated variance of the log hazard ratio. In Panel B, Kaplan–
Meier curves are shown for survival free of myocardial infarction for the
pooled population during a 5-year period in each of the stent groups.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .
14 Trials of Sirolimus-Elu ting Stents ver sus Bare-Me tal Stents
n engl j med 356;10 www.nejm.org march 8, 2007
1035
either died or had a myocardial infarction, as com-
pared with 252 patients with bare-metal stents.
Overall, use of sirolimus-eluting stents was as-

sociated with a hazard ratio for death or myo-
cardial infarction of 0.97 (95% CI, 0.81 to 1.16;
P = 0.76), as compared with use of bare-metal
stents. Figure 2B shows the overall 5-year curves
for survival free of myocardial infarction in the
two study groups.
Figure 3A shows the absolute numbers of pa-
tients who died, had a myocardial infarction, or
required reintervention in each trial according to
treatment group, with the hazard ratio for each
trial. In total, 331 patients with sirolimus-eluting
stents died, had a myocardial infarction, or re-
quired reintervention, as compared with 649 pa-
tients with bare-metal stents. Overall, the use of
sirolimus-eluting stents was associated with a
hazard ratio for death, myocardial infarction, or
reintervention of 0.43 (95% CI, 0.34 to 0.54;
P<0.001), as compared with the use of bare-metal
stents. Although the point estimates for individ-
ual trials all favored sirolimus-eluting stents,
there was a significant heterogeneity across trials
with a high I
2
value. Figure 3B shows the overall
5-year curves for survival free of myocardial
infarction and reintervention in the two study
groups.
No significant interaction between treatment
groups and the diagnosis of diabetes was ob-
served for any of the three end points of the

study, including death (P = 0.19), death or myocar-
dial infarction (P = 0.39), and death, myocardial
infarction, or reintervention (P = 0.49). We none-
theless performed a separate analysis of the rate
of death in the subgroup of patients with diabetes.
Figure 4A shows the absolute numbers of deaths
in each trial by treatment group, with the hazard
ratio for the subgroup of patients with diabetes in
each trial. There was no significant heterogeneity
across trials. In total, 59 patients with diabetes
and sirolimus-eluting stents died, as compared
with 56 patients with diabetes and bare-metal
stents. The overall hazard ratio associated with
sirolimus-eluting stents was 1.27 (95% CI, 0.83 to
1.95; P = 0.26). Figure 4B shows the overall 5-year
survival curves in the subgroup of patients with
diabetes.
Stent thrombosis (as defined by the individual
22p3
0.1 1.0
10.0
Sirolimus Stent
Better
Bare-Metal
Stent Better
Hazard RatioTrial
Sirolimus
Stent
Bare-Metal
Stent

P(heterogeneity)=0.001
I
2
=62%
P(overall effect)<0.001
Probability of Survival Free of Myocardial
Infarction and Reintervention (%)
80
90
70
60
50
0
0 1 2 3 4
5
Years after Randomization
Sirolimus stent
Bare-metal stent
100
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35610
No. of events/total no. of patients
BASKET
C-SIRIUS
DECODE
DIABETES
E-SIRIUS
Pache et al.
PRISON II
RAVEL
SCANDSTENT
SCORPIUS
SESAMI
SIRIUS
STRATEGY

TYPHOON
Overall
32/264
5/50
8/54
10/80
26/175
59/250
6/100
20/120
7/163
15/95
11/160
91/533
17/87
24/355
331/2486
41/281
14/50
11/29
33/80
58/177
73/250
25/100
28/118
51/159
32/98
26/160
164/525
31/88

62/357
649/2472
0.43 (0.34 to 0.54)
A
B
No. at Risk
Sirolimus stent
Bare-metal stent
491
395
921
773
682
621
1099
902
1891
1639
2486
2472
Figure 3. Hazard Ratios for Death, Myocardial Infarction, or Reintervention
and Kaplan–Meier Curves for Survival Free of Myocardial Infarction and
Reintervention.
Panel A shows significant heterogeneity in the effect of treatment result-
ing from the differing magnitude of risk reduction observed in patients
with sirolimus-eluting stents among the 14 trials. Hazard ratios are
shown on a logarithmic scale. The size of each square is proportional to
the weight of the individual study, measured as the inverse of the esti-
mated variance of the log hazard ratio. In Panel B, Kaplan–Meier curves
are shown for survival free of myocardial infarction and reintervention

for the pooled population during a 5-year period in each of the stent
groups.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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T h e n e w e n g l a n d j o u r na l o f m e d i c i n e
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1036
trials) was observed in 65 patients (34 with siro-
limus-eluting stents and 31 with bare-metal
stents). The hazard ratio for stent thrombosis was
1.09 (95% CI, 0.64 to 1.86; P = 0.75). After the
first year, stent thrombosis occurred in nine pa-
tients, eight of whom had sirolimus-eluting stents
(Fig. 5A). Over the 4-year period after the first
year following the procedure, the overall risk of
stent thrombosis was 0.6% (95% CI, 0.3 to 1.2)
in the sirolimus-stent group and 0.05% (95% CI,
0.01 to 0.4) in the bare-metal–stent group (P = 0.02).
Figure 5B shows the curves of probability of
stent thrombosis in the two study groups after
the trial-defined minimum duration of recom-
mended use of dual antiplatelet therapy (
Table 1
).
The overall risk of stent thrombosis during 4 years
after this time was 0.8% (95% CI, 0.5 to 1.5) in
the sirolimus-stent group and 0.3% (95% CI, 0.1
to 0.6) in the bare-metal–stent group (P = 0.16).
In 8 of the 14 trials, data for patients under-
going target-lesion revascularization were cen-

sored with respect to the subsequent assessment
of stent thrombosis. This censoring resulted in
the exclusion of five additional cases of stent
thrombosis, all in the bare-metal–stent group.
In contrast, in the other six trials, such censoring
did not occur, which resulted in the inclusion of
one case of stent thrombosis that occurred after
target-lesion revascularization in the sirolimus-
stent group.
Disc u s sion
In our study, we analyzed individual data for pa-
tients with coronary heart disease from 14 ran-
domized trials comparing sirolimus-eluting stents
with bare-metal stents. We found that the use of
sirolimus-eluting stents was associated with rates
of death alone or combined with myocardial in-
farction that were similar to those observed with
the use of bare-metal stents. Sirolimus-eluting
stents were also associated with a sustained re-
duction in the need for reintervention but with
an overall risk of stent thrombosis that was at
least as high as that seen with bare-metal stents.
Several previous analyses of trials comparing
drug-eluting stents and bare-metal stents in pa-
tients with coronary artery disease have been re-
ported.
5-7,29-34
In these previous studies, aggre-
gate data from published reports, rather than data
from individual patients, were examined. The

superiority of analysis of data from individual
patients over meta-analysis of lumped study out-
comes has been emphasized.
35-38
In particular for
survival data, the lack of adjustment for censor-
ing leads to an imprecise estimate of the overall
treatment effect and interstudy heterogeneity.
39

Access to data for individual patients also makes
22p3
1.27 (0.83 to 1.95)
0.1 1.0
10.0
Sirolimus Stent
Better
Bare-Metal
Stent Better
Hazard RatioTrial
Sirolimus
Stent
Bare-Metal
Stent
P(heterogeneity)=0.37
I
2
=7%
P(overall effect)=0.26
Probability of Survival (%)

80
90
70
60
50
0
0 1 2 3 4
5
Years after Randomization
Sirolimus stent
Bare-metal stent
100
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Enon
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35610
No. of events/total no. of patients
BASKET
C-SIRIUS
DECODE
DIABETES
E-SIRIUS
Pache et al.
PRISON II
RAVEL
SCANDSTENT
SCORPIUS
SESAMI
SIRIUS
STRATEGY
TYPHOON
Overall
3/41
1/12
0/54
7/80
2/33

9/72
1/11
6/19
0/29
5/95
2/28
20/131
2/15
1/55
59/675
1/60
0/12
2/29
5/80
3/48
12/82
1/16
2/25
0/29
4/98
6/37
15/148
3/11
2/61
56/736
A
B
No. at Risk
Sirolimus stent
Bare-metal stent

117
141
236
292
167
235
335
386
564
614
675
736
Figure 4. Hazard Ratios for Death in a Subgroup of Patients with Diabetes
and Kaplan–Meier Curves for Overall Survival.
In Panel A, hazard ratios are shown on a logarithmic scale. The size of each
square is proportional to the weight of the individual study, measured as
the inverse of the estimated variance of the log hazard ratio. In Panel B,
Kaplan–Meier curves are shown for survival for the pooled subgroup of
patients with diabetes during a 5-year period in each of the stent groups.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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14 Trials of Sirolimus-Elu ting Stents ver sus Bare-Me tal Stents
n engl j med 356;10 www.nejm.org march 8, 2007
1037
it possible to analyze the timing of events. We
made an extensive effort to identify and incorpo-
rate all trials comparing sirolimus-eluting stents
with bare-metal stents. As a result, we believe that
we have reduced the likelihood of study-selection
bias, the major risk of any meta-analysis, which

may have been present in previous reports.
The effect of the use of sirolimus-eluting stents
on long-term mortality has not previously been
established. Contrary to the expectation that pre-
vention of restenosis by sirolimus-eluting stents
might lead to improved survival, recent reports
suggested that sirolimus-eluting stents were as-
sociated with an increased rate of death as early
as 2 years after the procedure.
5,6
Although this
finding was not statistically significant, it gener-
ated much concern among the medical commu-
nity.
40
Our study shows no difference in mortality
between patients with sirolimus-eluting stents and
those with bare-metal stents during a 5-year pe-
riod. The same finding was true for the combined
end point of death or myocardial infarction.
No significant increase in the overall rate of
stent thrombosis was seen with sirolimus-eluting
stents. However, this complication was signifi-
cantly more frequent in patients with sirolimus-
eluting stents after the first year following the
procedure, a finding that was consistent with
another recent report.
41
This difference is chrono-
logically associated with the end of the protocol-

specified interval of dual antiplatelet therapy with
thienopyridines and aspirin. Although an accu-
rate assessment of this issue cannot be made
without knowledge of the actual timing of dis-
continuation of thienopyridine therapy in individ-
ual patients, our findings, as well as other recent-
ly published observations,
42
may suggest the need
for a longer duration of dual antiplatelet therapy
in patients receiving sirolimus-eluting stents.
As noted, there were another five cases of
stent thrombosis that were censored from the
analysis of the original trials because they oc-
curred after target-lesion revascularization. One
case of stent thrombosis that was included in our
count would have been excluded if such censoring
had been applied to all the trials. Whether such
cases of stent thrombosis should be included in
comparisons of this kind is open to question.
Proponents of inclusion would argue that post-
revascularization episodes of stent thrombosis
are an inseparable part of the experience of re-
ceiving a stent and that such episodes are more
common with bare-metal stents because target-
lesion revascularization is required more often in
patients with such stents. The argument for ex-
cluding such episodes is that they may have oc-
curred not as a result of the original stent choice,
but as a result of the subsequent revasculariza-

tion procedure, and thus that they do not reflect
the biologic effects of the specific stent type.
Our observation that there is no late difference
in hard end points (death or myocardial infarc-
tion) despite an increase in late stent thrombosis
22p3
Probability of Stent Thrombosis (%)
1
2
0
0 1 2 3 4
5
Years after Minimum Duration of Recommended
Dual Antiplatelet Therapy
Sirolimus stent
Bare-metal stent
3
Probability of Stent Thrombosis (%)
1
2
0
0 1 2 3 4
5
Years after Randomization
Sirolimus stent
Bare-metal stent
3
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35610
A
B
No. at Risk
Sirolimus stent
Bare-metal stent
987

1015
594
584
1045
1055
1593
1605
2403
2381
No. at Risk
Sirolimus stent
Bare-metal stent
533
523
1021
1039
761
838
1208
1201
2042
2046
2486
2472
Figure 5. Kaplan–Meier Curves for Stent Thrombosis in the Pooled Population
According to Stent Type and the Duration of Dual Antiplatelet Therapy.
Panel A shows that after the first year following the index procedure, stent
thrombosis occurred in eight patients in the sirolimus-stent group and in
only one patient in the bare-metal–stent group. Panel B shows the proba-
bility of stent thrombosis after the use of a trial-defined minimum duration

of recommended dual antiplatelet therapy, according to stent type.
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T h e n e w e n g l a n d j o u r na l o f m e d i c i n e
n engl j med 356;10 www.nejm.org march 8, 2007
1038
associated with sirolimus-eluting stents may be
explained by the small proportion of patients with
this complication in the trials. Also, the negative
effect of late stent thrombosis on clinical out-
come might have been offset by the reduction in
the need for reintervention with the sirolimus-
eluting stent and, consequently, by the exposure
of a lower number of patients to postprocedural
complications, as suggested by recent analyses.
43
We paid special attention to patients with dia-
betes through a prespecified subgroup analysis.
Patients with diabetes are at increased risk for
adverse events after PCI,
44,45
and aortocoronary
bypass surgery is often considered to be a better
treatment option for them. The effect of drug-
eluting stents on the long-term outcome of pa-
tients with diabetes is not known. In the Siroli-
mus-Coated Bx Velocity Balloon-Expandable Stent
in the Treatment of De Novo Native Coronary
Artery Lesions (SIRIUS) trial, the largest trial in
our analysis, patients with diabetes continued to

have a relatively high rate of restenosis even after
receiving drug-eluting stents.
21
In our study, there
was no statistical interaction between the presence
of diabetes and the effect of sirolimus-eluting
stents on the outcome of patients, including the
rate of death. However, when we analyzed mor-
tality in the subgroup of patients with diabetes,
there was a trend toward a higher hazard ratio
in patients with sirolimus-eluting stents. This ob-
servation suggests that patients with diabetes
should be observed and followed especially care-
fully after treatment with sirolimus-eluting stents.
It also justifies further collection of data on the
long-term outcome of patients with diabetes who
are treated with such stents. In addition, it will
be important to evaluate whether other available
or new drug-eluting stents may offer better re-
sults to patients with diabetes.
In conclusion, the use of sirolimus-eluting
stents did not have a significant effect on overall
long-term survival or on survival free of myocar-
dial infarction, as compared with bare-metal
stents. There was a sustained reduction in the
need for reintervention after the placement of
sirolimus-eluting stents. The risk of stent throm-
bosis was at least as great as that seen with bare-
metal stents.
Supported by Deutsches Herzzentrum, Munich, Germany.

Dr. Kastrati reports receiving lecture fees from Bristol-Myers
Squibb, Cordis, GlaxoSmithKline, Lilly, Medtronic, Novartis, and
Sanofi-Aventis; Dr. Valgimigli, lecture fees from Guilford and
Merck and grant support from Merck; Dr. Kelbæk, unrestricted
grant support from Cordis to fund part of the salary of a re-
search nurse; Dr. Pfisterer, lecture fees from Medtronic; and Dr.
Schömig, unrestricted grant support for the Department of Car-
diology he chairs from Amersham/General Electric, Bayerische
Forschungsstiftung, Bristol-Myers Squibb, Cordis, Cryocath,
Guidant, Medtronic, Nycomed, and Schering. No other potential
conflict of interest relevant to this article was reported.
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(Accessed February 9, 2007, at http://
www.fda.gov/ohrms/dockets/ac/06/slides/
2006-4253oph1_04_Stone.pdf.)
Carrozza JP Jr, Kuntz RE, Levine MJ,
et al. Angiographic and clinical outcome
of intracoronary stenting: immediate and
long-term results from a large single-cen-
ter experience. J Am Coll Cardiol 1992;20:
328-37.
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betes mellitus and the clinical and angi-
ographic outcome after coronary stent
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original article

The

new england journal

of

medicine

n engl j med

351;20

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11, 2004

2058

Angiotensin-Converting–Enzyme Inhibition
in Stable Coronary Artery Disease

The PEACE Trial Investigators*

The writing committee for the Prevention
of Events with Angiotensin Converting En-
zyme Inhibition (PEACE) Trial (Eugene

Braunwald, M.D., Harvard Medical School
and Brigham and Women’s Hospital, Bos-
ton; Michael J. Domanski, M.D., National
Heart, Lung, and Blood Institute, Bethesda,
Md.; Sarah E. Fowler, Ph.D., George Wash-
ington University, Rockville, Md.; Nancy L.
Geller, Ph.D., National Heart, Lung, and
Blood Institute; Bernard J. Gersh, M.D.,
Mayo Clinic Foundation, Rochester, Minn.;
Judith Hsia, M.D., George Washington
University, Washington, D.C.; Marc A. Pfef-
fer, M.D., Ph.D., Harvard Medical School
and Brigham and Women’s Hospital; Made-
line M. Rice, Ph.D., George Washington
University, Rockville, Md.; Yves D. Rosen-
berg, M.D., National Heart, Lung, and Blood
Institute; and Jean L. Rouleau, M.D., Univer-
sity of Montreal, Montreal) takes respon-
sibility for the content of this article. Ad-
dress reprint requests to Dr. Braunwald at
the TIMI Study Group, Brigham and Wom-
en’s Hospital, 350 Longwood Ave., Boston,
MA 02115.
*The investigators and research coordina-
tors who participated in the PEACE Trial
are listed in the Appendix.
N Engl J Med 2004;351:2058-68.

Copyright © 2004 Massachusetts Medical Society.

background

Angiotensin-converting–enzyme (ACE) inhibitors are effective in reducing the risk of
heart failure, myocardial infarction, and death from cardiovascular causes in patients
with left ventricular systolic dysfunction or heart failure. ACE inhibitors have also been
shown to reduce atherosclerotic complications in patients who have vascular disease
without heart failure.

methods

In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE)
Trial, we tested the hypothesis that patients with stable coronary artery disease and
normal or slightly reduced left ventricular function derive therapeutic benefit from the
addition of ACE inhibitors to modern conventional therapy. The trial was a double-
blind, placebo-controlled study in which 8290 patients were randomly assigned to
receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching
placebo (4132 patients).

results

The mean (±SD) age of the patients was 64±8 years, the mean blood pressure
133±17/78±10 mm Hg, and the mean left ventricular ejection fraction 58±9 percent.
The patients received intensive treatment, with 72 percent having previously undergone
coronary revascularization and 70 percent receiving lipid-lowering drugs. The incidence
of the primary end point — death from cardiovascular causes, myocardial infarction,
or coronary revascularization — was 21.9 percent in the trandolapril group, as com-
pared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group,
0.96; 95 percent confidence interval, 0.88 to 1.06; P=0.43) over a median follow-up
period of 4.8 years.

conclusions

In patients with stable coronary heart disease and preserved left ventricular function
who are receiving “current standard” therapy and in whom the rate of cardiovascular
events is lower than in previous trials of ACE inhibitors in patients with vascular dis-
ease, there is no evidence that the addition of an ACE inhibitor provides further benefit
in terms of death from cardiovascular causes, myocardial infarction, or coronary revas-
cularization.
abstract
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ace inhibition in coronary disease

2059
lockade of the renin–angioten-

sin system has been shown to prolong
survival and reduce adverse outcomes in
patients with systolic heart failure

1-3

or left ventric-
ular systolic dysfunction.

4-9

Indeed, angiotensin-
converting–enzyme (ACE) inhibitors have become
a cornerstone in the treatment of these patients.

10-12

In addition, post hoc analyses of patients from the
Studies of Left Ventricular Dysfunction (SOLVD)

13

and the Survival and Ventricular Enlargement
(SAVE) trials,

5,14

both randomized studies that in-
volved patients with moderate-to-severe left ven-
tricular dysfunction, showed a reduction in the rate
of acute myocardial infarction in patients who were
treated with an ACE inhibitor. These observations
raised the possibility that patients with coronary
artery disease might benefit from ACE-inhibitor
treatment, independently of their left ventricular

function.
More recent studies have suggested that patients
at high risk for coronary events indeed benefit from
ACE-inhibitor therapy. In the Heart Outcomes Pre-
vention Evaluation (HOPE)

15

and the European Trial
on Reduction of Cardiac Events with Perindopril in
Stable Coronary Artery Disease (EUROPA),

16

pa-
tients with coronary or other vascular disease or
with diabetes and another cardiovascular risk fac-
tor had reduced rates of death from cardiovascular
causes or acute myocardial infarction when as-
signed to an ACE inhibitor as compared with place-
bo. Although both of these trials enrolled patients
without a history of heart failure, many of the en-
rollees, especially those in the HOPE study, had an
increased risk of adverse cardiovascular events.
The goal of the Prevention of Events with Angio-
tensin Converting Enzyme Inhibition (PEACE) Trial
was to test whether ACE-inhibitor therapy, when
added to modern conventional therapy, would re-
duce the rate of nonfatal myocardial infarction,
death from cardiovascular causes, or revasculariza-

tion in low-risk patients with stable coronary artery
disease and normal or slightly reduced left ventric-
ular function.
The design of the PEACE Trial has been described
previously

17

and is summarized here. Inclusion and
exclusion criteria are shown in Table 1. This study
was designed by Drs. Pfeffer, Braunwald, Doman-
ski, Geller, and Verter. The data were held and ana-
lyzed by the clinical and statistical coordinating
center under the supervision of Dr. Fowler. The
manuscript was written by Dr. Braunwald, Dr. Pfef-
fer, and the other members of the writing commit-
tee. Drs. Fowler, Pfeffer, and Braunwald take re-
sponsibility for the data presented.

conduct of the trial

Patients underwent randomization from November
1996 to June 2000 and were followed up for as long
as 7 years (median, 4.8 years), until December 31,
2003. The study was conducted after approval from
the institutional review boards at 187 sites (listed in
the Appendix) in the United States (including Puerto
Rico), Canada, and Italy. Patients gave their written
informed consent to participate. An independent
data and safety monitoring board reviewed patient

safety data and interim results. A morbidity and
mortality review committee reviewed and classified
all outcomes.
In February 2002, given the increasing evidence
of the benefit of ACE inhibitors or angiotensin-
receptor blockers in patients with diabetes mellitus
and renal disease,

18-20

the steering committee, with-
out knowledge of the outcome data and with ap-
proval from the data and safety monitoring board,
advised the investigators to substitute open-label
ACE inhibitors for the masked study treatment in
patients with diabetes and either overt proteinuria
or hypertension and microalbuminuria.

end points

Fourteen thousand one hundred patients were re-
quired to test the hypothesis that an ACE inhibitor
would reduce the rate of the original primary end
point, which consisted of death from cardiovascu-
lar causes or nonfatal myocardial infarction. The
secondary end point was a composite of death from
cardiovascular causes, nonfatal myocardial infarc-
tion, or coronary revascularization. In October 1997,
after 1584 patients had undergone randomization,
the steering committee (without any knowledge of

outcome data from the trial) concluded that re-
cruiting 14,100 patients was not feasible and ex-
panded the primary end point to include coronary
revascularization. The sample size was reduced to
8100 patients, and the original primary end point
became a secondary end point.
The study prespecified five other end points
based on combinations of death from cardiovas-
cular causes, nonfatal myocardial infarction, revas-
cularization, unstable angina, new congestive heart
failure, stroke, peripheral vascular disease, and car-
b
methods
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diac arrhythmia. In post hoc analyses, the primary
end points of the HOPE

15

and EUROPA

16

studies,
as well as new-onset congestive heart failure re-
quiring hospitalization or causing death and new-
onset diabetes, were also examined.

recruitment and randomization

Potentially eligible subjects participated in a two-
week run-in phase during which they were request-
ed to take trandolapril (Mavik, Abbott Laboratories)
at a dose of 2 mg per day. They were then excluded
if their compliance was poor or if they had side ef-
fects or an abnormal rise in the serum concentra-

tion of creatinine or potassium. Consenting patients
who successfully completed the run-in phase were
randomly assigned to receive either trandolapril or
a matching placebo; randomization was performed
with the use of permuted blocks, stratified accord-
ing to clinical site.
At a visit six months after randomization, pa-
tients who had tolerated the dose of 2 mg per day
received a new six-month supply of study medica-
tion (trandolapril at a dose of 4 mg per day or match-
ing placebo). Patients continued to be evaluated
at six-month intervals for primary and secondary
end points and for compliance with their assigned
drug regimen. The patients, investigators, and staff
members remained blinded to the treatment as-
signments.

statistical analysis

With the revised sample size, the trial had 90 per-
cent power to detect an 18 percent relative reduc-
tion in the incidence of the primary end point, as-
suming a 19 percent cumulative incidence of the
revised primary end point in the placebo group,
when the log-rank test was used at a 0.05 level of
significance. The sample-size calculation, based on
the method of Shih,

21

assumed a 15 percent rate of
discontinuation of active treatment and a 15 per-
cent rate of crossover to active treatment.
The data and safety monitoring board reviewed
data related to safety and the primary end point
with use of the Lan–DeMets procedure

22

and an
O’Brien–Fleming spending function to control the
type I error

23

and recommended continuation of
the trial until its scheduled conclusion. Statistical
analyses of the primary and secondary end points
followed the intention-to-treat principle. Relative
risks, heterogeneity among strata, and interactions
between treatment assignment and covariates were
assessed by proportional-hazards regression.

24

All
reported P values are two-sided.

characteristics of the patients

Of the 8290 patients who underwent randomiza-
tion, 4158 were assigned to receive trandolapril and
4132 matching placebo. All but one patient in each
group began taking the assigned study medication.
Eleven patients (three in the trandolapril group and
eight in the placebo group) received study medica-
tion but did not return for a follow-up visit. The me-
dian follow-up period was 4.8 years in each group.
Most baseline characteristics were similar in the
two treatment groups (Table 2). Overall, the pa-
tients’ mean (±SD) age was 64±8 years and 18 per-
cent were women. Fifty-five percent had had a my-
ocardial infarction, 72 percent had undergone at
least one coronary-revascularization procedure, and
results

* ACE denotes angiotensin-converting enzyme.
† A subgroup of echocardiograms was reviewed by a core laboratory to confirm

eligibility.

Table 1. Eligibility Criteria.*
Inclusion criteria

Age 50 yr or older
Coronary artery disease documented by at least one of the following:
Myocardial infarction at least 3 mo before enrollment
Coronary-artery bypass grafting or percutaneous transluminal coronary
angioplasty at least 3 mo before enrollment
Obstruction of ≥50% of the luminal diameter of at least one native vessel

on coronary angiography
Left ventricular ejection fraction >40% on contrast or radionuclide ventricu-
lography or echocardiography, a qualitatively normal left ventriculogram,
or the absence of left ventricular wall-motion abnormalities on echocardi-
ography†
Toleration of the medication and successful completion of the run-in phase,
with ≥80% compliance with the medication

Exclusion criteria

Current use of or a current condition requiring use of an ACE inhibitor
or a contraindication to ACE inhibitors
Current use of an angiotensin II–receptor antagonist
Hospitalization for unstable angina within the preceding 2 mo
Valvular heart disease deemed to require surgical intervention
Coronary-artery bypass grafting or percutaneous transluminal angioplasty
within the preceding 3 mo
Planned elective coronary revascularization
Serum creatinine >2.0 mg/dl (177 µmol/liter)
Serum potassium >5.5 mmol/liter
Limited chance of 5-yr survival
Psychosocial condition precluding long-term adherence
Unable or unwilling to give consent
Female sex and of childbearing potential and not using contraception
Current use in a research trial of medication not approved by the U.S. Food
and Drug Administration or the Health Protection Branch of the Cana-
dian Department of National Health and Welfare
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ace inhibition in coronary disease

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* Plus–minus values are means ±SD. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To con-
vert the values for cholesterol to millimoles per liter, multiply by 0.02586.
† P<0.05 for the comparison with placebo.
‡ Race was self-declared.
§ Data on ejection fraction were available for 3952 patients in the trandolapril group and 3926 patients in the placebo group.

¶Four patients had ejection fractions between 30 percent and 50 percent.

Table 2. Baseline Characteristics of the Patients.*
Characteristic Trandolapril (N=4158) Placebo (N=4132)

Age (yr)
64±8 64±8
Age >75 yr (% of patients) 11 11
Female sex (% of patients) 19† 17
White race (% of patients)‡ 92 93
Country (% of patients)
United States and Puerto Rico 58 58

Canada 30 30
Italy 12 12
Medical history (% of patients)
Documented myocardial infarction 54 56
Coronary disease on angiography 61 61
Angina pectoris 70 71
Percutaneous coronary intervention 42 41
Coronary-artery bypass grafting 38 40
Percutaneous coronary intervention or coronary-artery bypass grafting 72 72
Diabetes 18† 16
Hypertension 46 45
Diabetes with a history of hypertension or diastolic blood pressure
≥90 mm Hg or systolic blood pressure ≥140 mm Hg
12 11
Stroke or transient ischemic attack 7† 6
Current cigarette smoking 14 15
Blood pressure before run-in phase (mm Hg)
Systolic 134±17 133±17
Diastolic 78±10 78±10
Diastolic blood pressure ≥90 mm Hg or systolic blood pressure
≥140 mm Hg (% of patients)
42 41
Laboratory values
Serum creatinine (mg/dl) 1.0±0.2 1.0±0.2
Serum cholesterol (mg/dl) 192±39 192±40
Ejection fraction (%)§ 58±10 58±9
Ejection fraction >40% and <50% (% of patients)§¶ 15 15
Medications (% of patients)
Calcium-channel blocker 36 35
Beta-blocker 60 60

Aspirin or antiplatelet medication 90 91
Lipid-lowering drug 70 70
Diuretic agent 13 13
Digitalis 4 4
Antiarrhythmic agent 2 2
Anticoagulant 5 5
Insulin 4 4
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* CI denotes confidence interval, MI myocardial infarction, CABG coronary-artery bypass grafting, and PCI percutaneous
coronary intervention.

† PCI included laser revascularization.

Table 3. Incidence of the Primary End Point and Its Components and of Death from All Causes.*
Outcome
Trandolapril
(N=4158)
Placebo
(N=4132)
Hazard Ratio
(95% CI) P Value

no. of patients (%)

Primary (death from cardiovascular causes, nonfatal MI,
CABG or PCI)

†


909 (21.9) 929 (22.5) 0.96 (0.88–1.06) 0.43
Death from cardiovascular causes 146 (3.5) 152 (3.7) 0.95 (0.76–1.19) 0.67
Nonfatal MI 222 (5.3) 220 (5.3) 1.00 (0.83–1.20) 1.00
CABG 271 (6.5) 294 (7.1) 0.91 (0.77–1.07) 0.24
PCI† 515 (12.4) 497 (12.0) 1.03 (0.91–1.16) 0.65
Death from noncardiovascular or unknown causes 153 (3.7) 182 (4.4) 0.83 (0.67–1.03) 0.09

Death from any cause 299 (7.2) 334 (8.1) 0.89 (0.76–1.04) 0.13

17 percent were known to have diabetes. A quantita-
tive ejection fraction was available for 95 percent of
the cohort, and the mean value was 58±9 percent;
for the others, a two-dimensional echocardiogram
was reported as showing normal left ventricular
function on qualitative assessment. Seventy percent
of patients were using lipid-lowering drugs. The av-
erage serum cholesterol concentration was 192 mg
per deciliter (5 mmol per liter).

follow-up

All patients were followed until the trial closeout
period (July 1, 2003, to December 31, 2003), until
death, or until they became lost to follow-up. Pa-
tients were considered lost to follow-up if they had
not been seen at a visit within one year before the
end of the study. One hundred thirty-four patients
(68 in the placebo group [1.6 percent] and 66 in
the trandolapril group [1.6 percent]) were lost to
follow-up. Overall, vital status was known for all
but 45 (0.5 percent) of the patients who underwent
randomization.

compliance

Among the patients who were randomly assigned
to the trandolapril group, 81.9 percent were taking

trandolapril or an open-label ACE inhibitor at one
year, 78.5 percent were doing so at two years, and
74.5 percent were doing so at three years. Among
the patients randomly assigned to the placebo
group, 1.5 percent were receiving an ACE inhibitor
at one year, 4.6 percent were doing so at two years,
and 8.3 percent were doing so at three years; 68.6
percent of the treated group and 77.7 percent of the
placebo group were taking the target dose of 4 mg
of trandolapril or placebo, respectively, per day. Of
the 2118 patients with diabetes at baseline or new-
onset diabetes by February 1, 2002, 402 (19.0 per-
cent) had taken an open-label ACE inhibitor before
February 1, 2002; 286 (13.5 percent) did so for the
first time after that date.

effects on blood pressure

The mean blood pressure on entry into the study (be-
fore the run-in phase) was 133±17/78±10 mm Hg
in the two groups combined. After 36 months, the
pressure had decreased by 1.4±0.3/2.4±0.2 mm Hg
in the placebo group and by 4.4±0.3/3.6±0.2
mm Hg in the trandolapril group. The changes in
systolic and diastolic pressures were significantly
different between the two groups at 36 months
(P<0.001).

primary end point

The incidence of the primary end point was 22.5
percent in the placebo group and 21.9 percent in
the trandolapril group (hazard ratio in the tran-
dolapril group, 0.96; 95 percent confidence inter-
val; 0.88 to 1.06; P=0.43) (Table 3 and Fig. 1). Ad-
justment for baseline characteristics (age, sex, and
the presence or absence of a history of myocardial
infarction, stroke or transient ischemic attack, or
diabetes) did not alter the results.
No benefit in terms of the primary end point
was observed among patients assigned to trandola-
pril in any subgroup defined according to age; sex;
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ace inhibition in coronary disease

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race; the presence or absence of a history of myo-
cardial infarction or of a previous revascularization
procedure; the presence or absence of diabetes; the

serum cholesterol or creatinine concentration; left
ventricular function; or the baseline use of diuretic
agents, digitalis, aspirin or antiplatelet medication,
beta-blockers, calcium-channel blockers, or lipid-
lowering drugs. A slight benefit was observed
among patients in the trandolapril group in whom
the systolic pressure before the run-in phase was
less than 140 mm Hg and the diastolic pressure less
than 90 mm Hg (hazard ratio as compared with pla-
cebo, 0.88; 95 percent confidence interval, 0.78 to
0.99); no benefit was observed among patients in
whom the systolic pressure before the run-in phase
was 140 mm Hg or higher or the diastolic pressure
90 mm Hg or higher (hazard ratio as compared
with placebo, 1.09; 95 percent confidence interval,
0.94 to 1.25; P=0.02 by a test for interaction). When
data for all the patients who received an open-label
ACE inhibitor were censored, the hazard ratio for
the primary end point in the trandolapril group
was 0.95 (95 percent confidence interval, 0.89 to
1.02; P=0.16). The results did not change when data
from patients with diabetes were censored at the
time they began receiving ACE inhibitors on an
open-label basis.

secondary end points and other outcomes

The estimated hazard ratios for all the prespecified
secondary end points in the trandolapril group, as
compared with the placebo group, ranged from

0.95 to 0.98, and none were statistically significant
(Table 4). Diabetes, although it was not a prespeci-
fied end point and although the analysis was not
adjusted for multiple comparisons, developed in
fewer of the patients assigned to receive trandola-
pril than of those assigned to receive placebo. In
addition, fewer patients in the trandolapril group
than in the placebo group were hospitalized with
or died of congestive heart failure.

side effects

Side effects leading to discontinuation of the study
medication occurred in 6.5 percent of the patients
in the placebo group and 14.4 percent of those in
the trandolapril group (P<0.001). The rates of cough
(39.1 percent vs. 27.5 percent, P<0.01) and syncope
(4.8 percent vs. 3.9 percent, P=0.04) were greater
in the trandolapril group than in the placebo group.
Angioedema occurred in five patients in the pla-
cebo group (two receiving ACE inhibitors on an
open-label basis) and eight patients in the trandola-
pril group.
In the PEACE Trial, 8290 patients with stable coro-
nary artery disease and normal or near-normal left
ventricular function were randomly assigned to re-
ceive placebo or trandolapril, and no significant
differences in the primary end point — a compos-
ite of death from cardiovascular causes, nonfatal
myocardial infarction, or revascularization — or in

prespecified secondary end points were observed.
In this trial, the ACE inhibitor trandolapril was used
at the dose that had been shown in the Trandolapril
Cardiac Evaluation (TRACE) Study

7


to improve sur-
vival and reduce the rate of cardiovascular events
and to reduce blood pressure in trials involving sub-
jects with hypertension.

25

Compliance with the
study medication in the PEACE Trial was similar to
that in other long-term trials of ACE inhibitors:
slightly less than 80 percent of the patients as-
signed to take an ACE inhibitor and about 5 per-
cent of those assigned to take placebo were receiv-
ing active treatment at two years. Randomization
to trandolapril was associated with a clear and sus-
tained reduction of 4.5 mm Hg in systolic pressure,
as compared with randomization to placebo, in
which a reduction of 1.5 mm Hg was observed. It
was also associated, in a post hoc analysis, with re-
discussion

Figure 1. Cumulative Incidence of the Primary End Point, According to

Treatment Group.
30
Incidence of Primary End Point (%)
20
25
15
10
5
0
0 1 2 3 4
65
Trandolapril
Placebo
Years after Randomization
No. at Risk
Trandolapril
Placebo
969
891
1963
1929
3079
3027
3506
3486
3752
3719
4017
3990
4158

4132
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ductions in the number of patients in whom diabe-
tes developed and the number who required hospi-
talization for the management of heart failure, as
has been observed with other ACE inhibitors.

4,18

These findings provide strong evidence of the phar-
macologic activity of the standard dose of trandola-
pril (4 mg per day).
The SAVE

5

and the SOLVD

2,4

trials demonstrat-
ed that ACE-inhibitor therapy reduced mortality and
the rate of development or intensification of heart
failure in patients with symptomatic heart failure
and those with asymptomatic left ventricular dys-
function. Despite the use of different ACE inhibi-
tors and inclusion criteria, both trials reported the
same intriguing secondary finding — that the rate
of subsequent myocardial infarction was approxi-
mately 20 percent lower among patients randomly
assigned to the ACE inhibitor than among those
assigned to a placebo.

5,13,14

These results suggest-

ed that inhibition of the renin–angiotensin system
may produce beneficial effects with respect to ath-
erosclerotic events. Since both of these trials were
conducted in patients with impaired left ventricu-
lar function and presumed activation of the renin–

* CI denotes confidence interval, MI myocardial infarction, CHF congestive heart failure, PEACE the Prevention of Events
with Angiotensin Converting Enzyme Inhibition Trial, HOPE the Heart Outcomes Prevention Evaluation,

15

and EUROPA
the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease.

16

† The analysis included 3432 patients in the trandolapril group and 3472 patients in the placebo group and excluded pa-

tients with diabetes at baseline.

Table 4. Incidence of Secondary End Points and Other Outcomes.*
Outcome
Trandolapril
(N=4158)
Placebo
(N=4132)
Hazard Ratio
(95% CI) P Value

no. of patients (%)

Planned analyses

Death from cardiovascular causes, nonfatal MI, revas-
cularization, or unstable angina
1060 (25.5) 1068 (25.8) 0.98 (0.90–1.07) 0.64
Death from cardiovascular causes, nonfatal MI, revas-
cularization, unstable angina, or new CHF
1091 (26.2) 1122 (27.1) 0.96 (0.88–1.04) 0.30
Death from cardiovascular causes, nonfatal MI, revas-
cularization, unstable angina, new CHF requir-
ing hospitalization, or stroke
1125 (27.1) 1164 (28.2) 0.95 (0.88–1.03) 0.23
Death from cardiovascular causes, nonfatal MI, revas-
cularization, unstable angina, new CHF requir-
ing hospitalization, stroke, or peripheral vascu-
lar disease requiring intervention, angioplasty,
bypass surgery, or aneurysm repair
1205 (29.0) 1243 (30.1) 0.95 (0.88–1.03) 0.23
Death from cardiovascular causes, nonfatal MI, revas-
cularization, unstable angina, new CHF, stroke,
peripheral vascular disease, or cardiac arrhyth-
mia requiring hospitalization
1284 (30.9) 1311 (31.7) 0.96 (0.89–1.04) 0.35
Death from cardiovascular causes or nonfatal MI
(original outcome in PEACE Trial)
344 (8.3) 352 (8.5) 0.97 (0.83–1.12) 0.67

Post hoc analyses

Death from cardiovascular causes, nonfatal MI, or stroke
(outcome in HOPE)
396 (9.5) 420 (10.2) 0.93 (0.81–1.07) 0.32
Death from cardiovascular causes, nonfatal MI, or cardiac
arrest (outcome in EUROPA)
346 (8.3) 356 (8.6) 0.96 (0.83–1.12) 0.62
CHF
As primary cause of hospitalization or death 115 (2.8) 152 (3.7) 0.75 (0.59–0.95) 0.02
As primary cause of hospitalization 105 (2.5) 134 (3.2) 0.77 (0.60–1.00) 0.05
As primary cause of death 15 (0.4) 25 (0.6) 0.59 (0.31–1.13) 0.11
Stroke 71 (1.7) 92 (2.2) 0.76 (0.56–1.04) 0.09
Onset of new diabetes† 335 (9.8) 399 (11.5) 0.83 (0.72–0.96) 0.01
Copyright © 2004 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 .

n engl j med

351;20

www.nejm.org november

11, 2004

ace inhibition in coronary disease

2065

angiotensin system, the applicability of these find-
ings to populations of patients with normal left ven-
tricular function remained conjectural.

Accordingly, three trials were conducted to test
the hypothesis that inhibition of the renin–angio-
tensin system with an ACE inhibitor in patients with
vascular disease who do not have overt heart failure
reduces the risk of major atherosclerotic events. In
HOPE, high-risk patients with vascular disease (in-
cluding coronary artery disease) or diabetes who
did not have heart failure and were not known to
have a low ejection fraction were randomly assigned
to receive either ramipril or placebo. The trial
showed a significant reduction (22 percent) in the
primary end point — death from cardiovascular
causes, nonfatal myocardial infarction, or stroke —
with ramipril.

15

Subsequently, the American Heart
Association modified secondary-prevention guide-
lines, recommending that ACE inhibitors be “con-
sidered for all patients with vascular disease.”

26

In EUROPA, patients with stable coronary artery
disease who did not have clinical evidence of heart
failure and who were at a lower risk than the pa-
tients in HOPE were randomly assigned to receive
perindopril or placebo.

16

The patients assigned to
the ACE inhibitor had a significant reduction (20
percent) in the primary end point — death from
cardiovascular causes, nonfatal myocardial infarc-
tion, or cardiac arrest. Thus, EUROPA showed that
the clinical benefits of ACE inhibitors could be ex-
tended to a population of patients with coronary ar-
tery disease who had a better prognosis than those
in HOPE.
In the third trial (the PEACE Trial, the subject of
the current report), 8290 patients with stable coro-
nary artery disease and normal or near-normal left
ventricular function were randomly assigned to re-
ceive trandolapril or placebo; ACE-inhibitor ther-
apy was not found to have a significant benefit. No
clinical benefit was observed in the trandolapril
group despite the reduction in blood pressure in
that group. To interpret the predominantly nega-
tive findings of this study in the context of the pos-
itive reports from both HOPE

15

and EUROPA,

16

it

is useful to compare the characteristics of the pa-
tients and the rates of events in those two trials
with those in the PEACE Trial (Fig. 2). At baseline,
the patients in the PEACE Trial had an average left
ventricular ejection fraction of 58 percent, and their
average creatinine and cholesterol concentrations
were normal. Their average blood pressure at
baseline was 133/78 mm Hg, which was the level
achieved with use of an ACE inhibitor in both
HOPE and EUROPA.
The patients in the PEACE Trial also received
more intensive management of risk factors than
did those in HOPE and EUROPA. At baseline, 70
percent of the patients (as compared with 29 percent
in HOPE and 56 percent in EUROPA) were receiv-
ing lipid-lowering therapy. Moreover, 72 percent of
the patients in the PEACE Trial, as compared with
54 percent in EUROPA and 40 percent in HOPE,
had undergone coronary revascularization before
enrollment; this more aggressive strategy might
have contributed to the lower risk of adverse events
in the PEACE Trial. Therefore, it is not surprising
that with more intensive treatment of coronary ar-
tery disease and risk-factor modification, adverse
cardiovascular outcomes in patients assigned to
placebo were substantially lower in PEACE than
they were in the other two trials. Indeed, among
patients assigned to take placebo, the fractions of
deaths that were deemed of cardiovascular cause
also reflect this difference, at 63 percent in HOPE,

59 percent in EUROPA, and 47 percent in PEACE,
as compared with 35 percent in a general popula-
tion matched according to age and sex with the
PEACE Trial cohort.

27

Furthermore, despite objec-
tive evidence of coronary artery disease among pa-
tients in the PEACE Trial and a history of myocar-
dial infarction in 55 percent of them, the annualized
rate of death from all causes was only 1.6 percent,
similar to that of an age- and sex-matched general
population.

27

Thus, we hypothesize that the PEACE Trial does
not demonstrate the benefits of ACE inhibition

Figure 2. Comparison of Outcomes in the PEACE Trial and HOPE.

PEACE denotes the Prevention of Events with Angiotensin Converting En-
zyme Inhibition Trial, HOPE the Heart Outcomes Prevention Evaluation,
and MI myocardial infarction.
Death from Cardiovascular
Causes, Nonfatal MI,
or Stroke (%)
20
10

5
15
0
0
1 2 3 4
5
Years of Follow-up
PEACE, placebo
HOPE, placebo
HOPE, active drug
(ramipril)
Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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